Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

Personnaz, J.; Piccolo, E.; Dortignac, A.; Iacovoni, J. S.; Mariette, J.; Polizzi, A.; Batut, A.; Deleruyelle, S.; Paccoud, R.; Moreau, E.; Martins, F.; Clouaire, T.; Benhamed, F.; Montagner, A.; Wahli, W. A.; Schwabe, R. F.; Yart, A.; Castan-Laurell, I.; Postic, C.; Moro, C.; Legube, G.; Lee, C.-H.; Guillou, H.; Valet, P.; Dray, C.; Pradere, J.-P.

doi:10.1101/2021.02.17.431446

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bioRxiv · 10.1101/2021.02.17.431446

Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

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Abstract

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXR activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXR. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXR axis during NAFLD.

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Personnaz, J., Piccolo, E., Dortignac, A., Iacovoni, J. S., Mariette, J., Polizzi, A., Batut, A., Deleruyelle, S., Paccoud, R., Moreau, E., Martins, F., Clouaire, T., Benhamed, F., Montagner, A., Wahli, W. A., Schwabe, R. F., Yart, A., Castan-Laurell, I., Postic, C., Moro, C., Legube, G., Lee, C.-H., Guillou, H., Valet, P., Dray, C., Pradere, J.-P.. 2021-02-17. Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor. https://doi.org/10.1101/2021.02.17.431446

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